| 11. |
- Ejeskär, Katarina, 1969, et al.
(författare)
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Introduction of in vitro transcribed ENO1 mRNA into neuroblastoma cells induces cell death.
- 2005
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Ingår i: BMC cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Neuroblastoma is a solid tumour of childhood often with an unfavourable outcome. One common genetic feature in aggressive tumours is 1p-deletion.The alpha-enolase (ENO1) gene is located in chromosome region 1p36.2, within the common region of deletion in neuroblastoma. One alternative translated product of the ENO1 gene, known as MBP-1, acts as a negative regulator of the c-myc oncogene, making the ENO1 gene a candidate as a tumour suppressor gene. METHODS: Methods used in this study are transfection of cDNA-vectors and in vitro transcribed mRNA, cell growth assay, TUNEL-assay, real-time RT-PCR (TaqMan) for expression studies, genomic sequencing and DHPLC for mutation detection. RESULTS: Here we demonstrate that transfection of ENO1 cDNA into 1p-deleted neuroblastoma cell lines causes' reduced number of viable cells over time compared to a negative control and that it induces apoptosis. Interestingly, a similar but much stronger dose-dependent reduction of cell growth was observed by transfection of in vitro transcribed ENO1 mRNA into neuroblastoma cells. These effects could also be shown in non-neuroblastoma cells (293-cells), indicating ENO1 to have general tumour suppressor activity.Expression of ENO1 is detectable in primary neuroblastomas of all different stages and no difference in the level of expression can be detected between 1p-deleted and 1p-intact tumour samples. Although small numbers (11 primary neuroblastomas), there is some evidence that Stage 4 tumours has a lower level of ENO1-mRNA than Stage 2 tumours (p = 0.01). However, mutation screening of 44 primary neuroblastomas of all different stages, failed to detect any mutations. CONCLUSION: Our studies indicate that ENO1 has tumour suppressor activity and that high level of ENO1 expression has growth inhibitory effects.
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| 12. |
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| 13. |
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| 14. |
- Gerlee, Philip, 1980, et al.
(författare)
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Autocrine signaling can explain the emergence of Allee effects in cancer cell populations
- 2022
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Ingår i: Plos Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 18:3
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Tidskriftsartikel (refereegranskat)abstract
- In many human cancers, the rate of cell growth depends crucially on the size of the tumour cell population. Low, zero, or negative growth at low population densities is known as the Allee effect; this effect has been studied extensively in ecology, but so far lacks a good explanation in the cancer setting. Here, we formulate and analyze an individual-based model of cancer, in which cell division rates are increased by the local concentration of an autocrine growth factor produced by the cancer cells themselves. We show, analytically and by simulation, that autocrine signaling suffices to cause both strong and weak Allee effects. Whether low cell densities lead to negative (strong effect) or reduced (weak effect) growth rate depends directly on the ratio of cell death to proliferation, and indirectly on cellular dispersal. Our model is consistent with experimental observations from three patient-derived brain tumor cell lines grown at different densities. We propose that further studying and quantifying population-wide feedback, impacting cell growth, will be central for advancing our understanding of cancer dynamics and treatment, potentially exploiting Allee effects for therapy.
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| 15. |
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| 16. |
- Krona, Cecilia, 1976, et al.
(författare)
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A novel 1p36.2 located gene, APITD1, with tumour-suppressive properties and a putative p53-binding domain, shows low expression in neuroblastoma tumours.
- 2004
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Ingår i: British journal of cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 91:6, s. 1119-30
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Tidskriftsartikel (refereegranskat)abstract
- Neuroblastoma is characterised by a lack of TP53 mutations and no other tumour suppressor gene consistently inactivated has yet been identified in this childhood cancer form. Characterisation of a new gene, denoted APITD1, in the neuroblastoma tumour suppressor candidate region in chromosome 1p36.22 reveals that APITD1 contains a predicted TFIID-31 domain, representing the TATA box-binding protein-associated factor, TAF(II)31, which is required for p53-mediated transcription activation. Two different transcripts of this gene were shown to be ubiquitously expressed, one of them with an elevated expression in foetal tissues. Primary neuroblastoma tumours of all different stages showed either very weak or no measurable APITD1 expression, contrary to the level of expression observed in neuroblastoma cell lines. A reduced pattern of expression was also observed in a set of various tumour types. APITD1 was functionally tested by adding APITD1 mRNA to neuroblastoma cells, leading to the cell growth to be reduced up to 90% compared to control cells, suggesting APITD1 to have a role in a cell death pathway. Furthermore, we determined the genomic organisation of APITD1. Automated genomic DNA sequencing of the coding region of the gene as well as the promoter sequence in 44 neuroblastoma tumours did not reveal any loss-of-function mutations, indicating that mutations in APITD1 is not a common abnormality of neuroblastoma tumours. We suggest that low expression of this gene might interfere with the ability for apoptosis through the p53 pathway.
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| 17. |
- Krona, Cecilia, 1976, et al.
(författare)
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Analysis of neuroblastoma tumour progression; loss of PHOX2B on 4p13 and 17q gain are early events in neuroblastoma tumorigenesis
- 2008
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Ingår i: International Journal of Oncology. - 1019-6439. ; 32:3, s. 575-583
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Tidskriftsartikel (refereegranskat)abstract
- Neuroblastomas are biologically and clinically heterogeneous tumours that most often occur sporadically in children at median age 2. The PHOX2B gene is implicated in the development of the autonomic nervous system and has been found to be infrequently mutated in sporadic neuroblastoma tumours and in some patients with hereditary neuroblastoma. We have screened a selected series of 36 paediatric tumours with presumed genetic predisposition, 34 of them neuroblastomas, for mutations in PHOX2B. A constitutional heterozygous missense mutation was found in a boy who developed bilateral adrenal tumours and stage 4 disease during infancy. The second allele of the PHOX2B locus was lost in the tumour DNA. Histopathological evaluation of the tumours suggested growth of two primary tumours, one with diploid DNA content and the other with tetraploid DNA content, i.e. a case of neuroblastoma stage 4M (multifocal tumour). However, array CGH (comparative genomic hybridization) data performed on both tumour masses from the patient instead supported a model where a common malignant precursor gave rise to the diploid tumour and subsequently the tetraploid tumour have progressed from the common precursor or by metastasis from the diploid tumour with additional genetic changes. The whole genome dosage analysis showed that the remaining alleles of PHOX2B had been lost in both tumours together with a specific 17q gain pattern. The tetraploid tumour had these features together with additional whole chromosomal loss of chromosomes 3, 9, 14, and 15. Based on the data presented here we suggest that loss of PHOX2B and 17q gain are early events in neuroblastoma tumourigenesis. We also propose investigators to re-analyze the rare cases of multifocal neuroblastomas with the array CGH technique for better understanding of the origin of these tumours.
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| 18. |
- Krona, Cecilia, 1976
(författare)
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Identification and characterization of candidate genes for neuroblastoma development
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neuroblastoma (NB) is the most common tumor during infancy. It arises from undifferentiated cells in the sympathetic nervous system and is characterized by both clinical and genetic heterogeneity. One of the features of NBs with unfavorable outcome is loss on distal chromosome 1p. The aim of this thesis was to identify genetic factors with relevance for NB tumorigenesis, with special emphasis on the tumor suppressor candidate region on chromosome 1p36.2. All known genes (UBE4B, KIF1B, PGD, CORT, DFFA and PEX14) in the hotspot NB tumor suppressor gene region on 1p36.22 were screened for mutations by capillary-based sequencing of DNA from a large series of NB tumors. The potential tumor suppressor properties of the genes ENO1, ICAT and CASP9, located close to this region, were also analyzed. A few mutations with predicted deleterious effects on protein function were found in the apoptotic regulator DFFA and in the UBE4B gene, which is involved in selective protein degradation. We were also able to show that expression of ENO1, DFFA, UBE4B and CASP9, critical for induction of the apoptotic cascade, is down-regulated in tumors with unfavorable outcome. We identified a novel gene, denoted APITD1, in 1p36.22; two alternative transcripts of this gene were abundantly expressed in normal adult and fetal tissues. Primary NB tumors showed either very weak or no measurable APITD1 expression and the lowest levels were detected in tumors with unfavorable outcome. The coding sequence of APITD1 was well-conserved in different species and no coding variations were found in primary NB tumors. Anti-proliferative and apoptotic effects were observed after over-expression of APITD1 and ENO1 in NB cell lines and in embryonal kidney- derived cells. A mutated ENO1 construct was used to show that the glycolytic enzyme α-enolase had as strong an effect on cell proliferation as the other translational product, MBP1, which is a negative regulator of the c-Myc oncogene. Biallelic inactivation of the transcription factor PHOX2B on chromosome 4p was found in a patient with multifocal NB, emphasizing the importance of early embryologic differentiation pathways in tumors of neural crest origin. A few rare mutations were found in genes with possible tumor suppressor functions. Several genes on 1p36.2 were also shown to be down-regulated in aggressive tumors. We therefore propose that the poor prognosis for NB patients with 1p deletions is a syngenic effect of mutations or transcriptional silencing of several genes in this region.
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| 19. |
- Krona, Cecilia, 1976, et al.
(författare)
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Screening for gene mutations in a 500 kb neuroblastoma tumor suppressor candidate region in chromosome 1p; mutation and stage-specific expression in UBE4B/UFD2.
- 2003
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 22:15, s. 2343-51
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Tidskriftsartikel (refereegranskat)abstract
- Deletion of a part of the short arm of chromosome 1 is one of the most common chromosomal rearrangements observed in neuroblastoma (NBL) tumors and it is associated with a poor prognosis. No NBL tumor suppressor gene has yet been identified in the region. Our shortest region of overlap of deletions, ranging from marker D1S80 to D1S244, was shown to partly overlap a 500 kb region that was homozygously deleted in a NBL cell line. We have screened seven genes known to reside in or very close to this overlap consensus region, UBE4B/UFD2, KIF1B, DFFA, PGD, CORT, PEX14, and ICAT, for coding mutations in NBL tumor DNA. A few deviations from the reference sequences were identified; most interestingly being a splice site mutation that was detected in UBE4B/UFD2 in a stage 3 NBL with a fatal outcome. This mutation was neither present in the patients constitutional DNA nor in any of 192 control chromosomes analysed. Also, the expression of UBE4B/UFD2 was markedly diminished in the high-stage/poor-outcome tumors as compared to the low-stage/favorable-outcome tumors. Overall, the number of amino-acid changes in the genes of the region was low, which shows that mutations in these genes are rare events in NBL development. Given the data presented here, UBE4B/UFD2 stands out as the strongest candidate NBL tumor suppressor gene in the region at this stage.
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| 20. |
- Mega, Alessandro, et al.
(författare)
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Astrocytes enhance glioblastoma growth.
- 2020
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Ingår i: Glia. - : Wiley. - 0894-1491 .- 1098-1136. ; 68:2, s. 316-327
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma (GBM) is a deadly disease with a need for deeper understanding and new therapeutic approaches. The microenvironment of glioblastoma has previously been shown to guide glioblastoma progression. In this study, astrocytes were investigated with regard to their effect on glioblastoma proliferation through correlative analyses of clinical samples and experimental in vitro and in vivo studies. Co-culture techniques were used to investigate the GBM growth enhancing potential of astrocytes. Cell sorting and RNA sequencing were used to generate a GBM-associated astrocyte signature and to investigate astrocyte-induced GBM genes. A NOD scid GBM mouse model was used for in vivo studies. A gene signature reflecting GBM-activated astrocytes was associated with poor prognosis in the TCGA GBM dataset. Two genes, periostin and serglycin, induced in GBM cells upon exposure to astrocytes were expressed at higher levels in cases with high "astrocyte signature score". Astrocytes were shown to enhance glioblastoma cell growth in cell lines and in a patient-derived culture, in a manner dependent on cell-cell contact and involving increased cell proliferation. Furthermore, co-injection of astrocytes with glioblastoma cells reduced survival in an orthotopic GBM model in NOD scid mice. In conclusion, this study suggests that astrocytes contribute to glioblastoma growth and implies this crosstalk as a candidate target for novel therapies.
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